Using immunochemical methods, our laboratory has established that four proteins become detectable in the plasma of pregnant women, which are not found in plasma from non-pregnant untreated normal women or men. We have partially purified and characterized three of these pregnancy- associated plasma proteins (PAPP's), and have shown that their molecular weights are approximately 20,000, 110,000 and 750,000. The fourth PAPP is regularly visualized only by the technic of crossed- immunoelectrophoresis, which requires large volumes of antiserum; the latter is presently available only in modest amounts. Analogous PAPP's have been observed by us in the plasma of pregnant rats and mice. The latter cross-react immunologically with each other, but not with the human PAPP's. The proposed research is aimed at clarifying the biological role of each of these PAPP's in the gestational process, and determining the potential pathological significance of excessive or insufficient levels of any of these proteins in diseases of pregnancy. As examples, one series of experiments will analyze the pathological effects of PAPP depletion in rats and mice by administration of specific antibodies to each of the rat or mouse PAPP's, and studying their abortifacient or contraceptive properties. A reciprocal study will examine the changes brought about in rats and mice by administration of large amounts of each purified PAPP during pregnancy. After establishing the range of each PAPP during the course of normal human pregnancy, the potential pathogenic significance of abnormal levels of each PAPP will be determined in a correlative study with plasma taken from patients with well-defined disorders of pregnancy, e.g., toxemia, habitual abortion, etc. In addition, the PAPP's will be more completely purified and characterized, and their sites of synthesis (tissue and cellular) will be established immunohistochemically.